Engineered bacteria for therapeutic applications would benefit from control mechanisms that confine the growth of the bacteria within specific tissues or regions in the body. Here we show that the tropism of engineered bacteria can be enhanced by coupling bacterial growth with genetic circuits that sense oxygen, pH or lactate through the control of the expression of essential genes. Bacteria that were engineered with pH or oxygen sensors showed preferential growth in physiologically relevant acidic or oxygen conditions, and reduced growth outside the permissive environments when orally delivered to mice. In syngeneic mice bearing subcutaneous tumours, bacteria engineered with both hypoxia and lactate biosensors coupled through an AND gate showed increased tumour specificity. The multiplexing of genetic circuits may be more broadly applicable for enhancing the localization of bacteria to specified niches.

用于治疗应用的工程细菌将受益于将细菌生长限制在身体特定组织或区域内的控制机制。在这里，我们表明，通过控制必需基因的表达，将细菌生长与感知氧气、pH 或乳酸的遗传回路结合起来，可以增强工程细菌的嗜性。用 pH 或氧传感器设计的细菌在生理相关的酸性或氧气条件下表现出优先生长，并在口服给予小鼠时在允许的环境之外减少生长。在携带皮下肿瘤的同基因小鼠中，通过与门耦合的缺氧和乳酸生物传感器工程改造的细菌显示出增加的肿瘤特异性。